The critical importance of neuronal connectivity and its qualitative and quantitative aspects regarding neuronal activation have been recognized in the central regulation of energy balance. In non-human primates, and subsequently in transgenic mice, we revealed a rapid synaptic reorganization of the inputs of key hypothalamic peptidergic systems. The quantitative and qualitative reorganization of these synapses corresponded to the putative activity levels of the respective circuits in the face of changing metabolic state. The electrophysiological properties of these peptidergic systems closely reflected their qualitative and quantitative synaptic input organization and re-organization during various metabolic states. We conclude that the changing activity levels of hypothalamic peptidergic systems during changing metabolic states are determined, at least in part, by synaptic reorganization of their inputs triggered by the metabolic signal, leptin. Our central hypothesis is that leptin's effect on synaptic plasticity is mediated by the long form of leptin receptor (LRb) that activates the STAT-3 signaling pathway. We also predict that animals that develop diet-induced obesity exhibit altered synaptic organization of key peptidergic neuronal populations that will correspond to their altered electrophysiological characteristics. The following specific aims are proposed to test our hypotheses. Specific Aim 1: To reveal if (a) leptin-induced synaptic plasticity in the arcuate nucleus is impaired in mice with mutations in leptin signaling, (b) circulating leptin affects synaptic plasticity in a dose-dependent manner, and (c), acute leptin action on synaptic organization is long lasting. Specific Aim 2: To unmask molecular correlates of synaptic plasticity induced by leptin. Specific Aim 3: To determine if the synaptic organization and electrophysiological properties of the hypothalamic peptidergic neurons are altered in mice with diet-induced obesity. In all studies of Specific Aims 1-3, the parameters of synaptology and gene expression in each animal will be analyzed in conjunction with the animals' other metabolic characteristics, including feeding behavior, energy expenditure and blood hormonal and nutrient profiles. The understanding of the regulation and molecular mechanism of synaptic rearrangement caused by leptin will offer previously unsuspected targets for development of therapies against a variety of metabolic disorders, including obesity.